Chapter 3 – Treatment of transplant-eligible patients

Contributors: Mohamad Mohty, Florent Malard, Jean-Luc Harousseau

Multiple myeloma (MM) patients up to the ages of 65–70 years without prohibitive comorbidities are eligible for autologous stem cell transplantation (auto-SCT). For these patients initial treatment can typically be divided into four phases: induction therapy, intensification with high-dose treatment (HDT) plus auto-SCT, consolidation, and maintenance. These four phases will be discussed in this chapter, as well as the role of allogeneic stem cell transplantation (allo-SCT) in MM patients.

1 – Induction therapy

The objectives of induction treatment prior to HDT/auto-SCT are to reduce the tumor burden in order to increase the post HDT/auto-SCT complete remission rate and to decrease the plasma cell marrow infiltration to improve the quality of the graft.

The ideal induction treatment should be well tolerated and should spare normal hematopoietic precursors. Prior to the introduction of novel agents, alkylating agents were avoided due to their hematopoietic toxicity and the standard induction regimen was dexamethasone-based, either high-dose dexamethasone alone, or a combination of dexamethasone with non-alkylating cytotoxic agents, such as doxorubicin and vincristine in the so-called VAD regimen [1]. A number of randomized studies have demonstrated the superiority of induction regimens containing one or two novel agents (thalidomide or bortezomib) compared with VAD-based regimens (Table 3.1) [2–5].

With these new regimens, pre-auto-SCT response rates were superior, with higher complete response (CR) rates, as well as higher CR plus n-CR (near-complete response) or very good partial response (VGPR) rates. More importantly, this better efficacy translated into higher CR or CR plus n-CR or VGPR rates post-transplantation. Therefore, VAD is no longer considered the standard induction treatment [10,11].

Table 3.1 Induction regimens

*p-value statistically significant. Information regarding p-values not available. p-value VTD vs TD statistically significant. ASCT, autologous stem-cell transplantation; CR, complete response; CTD, cyclophosphamine-thalidomine-dexamethasone; CVAD, cyclophosphamine-vincristine-doxorubicin-dexamethasone; dex, dexamethasone; n/a, non-applicable; PAD, bortezomib-doxorubicin-dexamethasone; TAD, thalidomine-doxorubicin-dexamethasone; TD, thalidomine-dexamethasone; VAD, vincristine-doxorubicin-dexamethasone; VBAD, vincristine-carmustine-doxorubicin-dexamethasone; VBMCP, vincristine-carmustine-melphalan-cyclophosphamine-prednisone; VD, bortezomib-dexamethasone; VGPR, very good partial response; vs, versus; VTD, bortezomib-thalidomine-dexamethasone. Adapted from © the Ferrata Storti Foundation. All rights reserved. Mohty and Harousseau [9].

Three randomized studies have compared a two-drug induction (thalidomide and dexamethasone [TD], or bortezomib and dexamethasone [VD]) with a three-drug regimen (bortezomib, thalidomide, and dexamethasone [VTD]) [6,7,12]. In the three studies VTD was significantly superior to the two-drug regimen and is now considered a standard induction regimen (Table 3.1), although in the study by Rosiñol et al [12] VTD was not able to overcome the poor prognosis impact of high-risk cytogenetics. In addition, there is no evidence that four-drug regimens are superior and they may even be more toxic [13,14].

The better response rate observed with new regimens is related to a better efficacy across all prognostic subgroups, including international staging system (ISS) 3 and poor-risk cytogenetics [4,6]. There is currently no direct evidence that the higher CR plus n-CR rate achieved with these new regimens translates into a longer progression-free survival (PFS) because in all of these studies there were different post-auto-SCT treatments. However, there is an indirect argument in favor of the prognostic impact of a better induction treatment: the Intergroupe Francophone du Myélome (IFM) group has shown that achieving at least a higher VGPR rate after induction is associated with a longer PFS [15]. New induction regimens with lenalidomide (RVD) and carfilzomib (KRD) are under evaluation and might be even more attractive given the depth of the response that could be achieved. While these triple combinations have not yet been compared to VTD in randomized trials, the latest IFM2009 randomized trial suggests that RVD may be a promising induction regimen [16]. In the latter trial, patients received induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD or high-dose melphalan plus SCT followed by two additional cycles of RVD. Patients in both groups received maintenance therapy with lenalidomide for 1 year. The rate of CR was 48% in the RVD-alone group. The rate of CR or VGPR in the RVD-alone group was 45% after the induction phase, 69% after the consolidation phase, and 76% after the maintenance phase. Minimal residual disease (MRD) was not detected in 65% of the patients in the RVD-alone group. These results are likely to establish RVD as a powerful induction regimen in the near future.